SummaryInvolvement of the central nervous system (CNS) in multiple myeloma (MM) is a rare complication, with reported survival of <6 months. This report describes 37 MM patients with leptomeningeal and/or parenchymal brain involvement treated at our institution and identifies factors associated with long-term survival. From January 1999 to December 2010, 37 patients with CNS MM were evaluated at our institution. Clinical characteristics, treatment and survival were retrospectively collected. CNS disease was present at MM diagnosis in 24% and at relapse in 76%. Plasma cell leukemia (40%) and skull plasmacytomas (65%) were common, suggesting haematological and contiguous spread. Intrathecal (IT) chemotherapy was used in 81%, cranial and/or spinal irradiation in 78%, and various systemic therapies [immunomodulatory agents (IMiDs) (51%), cisplatin-based (DPACE; cisplatin, doxorubicin, cyclophosphamide, etoposide) (27%), bortezomib (19%), alkylators (11%), dexamethasone alone (8%), auto-transplant (5%)]. Median survival from CNS disease was only 4Á6 months [95% confidence interval (CI): 2Á8-6Á7]; however, nine patients had prolonged survival (median: 17Á1 months, 95% CI: 13Á2-67Á4). In general, these long-term survivors were treated with radiotherapy, multi-dosing IT chemotherapy, and IMiD-containing therapy. CNS MM is a highly aggressive disease but in our experience, long-term survival can be achieved with the combination of multi-dosing IT chemotherapy, radiation and IMiD-based therapy.
We have created a molecular resource of genes expressed in primary malignant plasma cells using a combination of cDNA library construction, 5 end single-pass sequencing, bioinformatics, and microarray analysis. In total, we identified 9732 nonredundant expressed genes. This dataset is available as the Myeloma Gene Index (www.uhnres.utoronto.ca/akstewart_lab). Predictably, the sequenced profile of myeloma cDNAs mirrored the known function of immunoglobulin-producing, highrespiratory rate, low-cycling, terminally differentiated plasma cells. Nevertheless, approximately 10% of myeloma-expressed sequences matched only entries in the database of Expressed Sequence Tags (dbEST) or the high-throughput genomic sequence (htgs) database. Numerous novel genes of potential biologic significance were identified. We therefore spotted 4300 sequenced cDNAs on glass slides creating a myeloma-enriched microarray. Several of the most highly expressed genes identified by sequencing, such as a novel putative disulfide isomerase (MGC3178), tumor rejection antigen TRA1, heat shock 70-kDa protein 5, and annexin A2, were also differentially expressed between myeloma and B lymphoma cell lines using this myelomaenriched microarray. Furthermore, a defined subset of 34 up-regulated and 18 down-regulated genes on the array were able to differentiate myeloma from nonmyeloma cell lines. These not only include genes involved in B-cell biology such as syndecan, BCMA, PIM2, MUM1/IRF4, and XBP1, but also novel uncharacterized genes matching sequences only in the public databases. In summary, our expressed gene catalog and myelomaenriched microarray contains numerous genes of unknown function and may complement other commercially available arrays in defining the molecular portrait of this hematopoietic malignancy.
The role of a second autologous stem cell transplant (ASCT) as salvage therapy is unclear, particularly with the availability of novel agents to treat progressive multiple myeloma (MM). We retrospectively reviewed all MM patients who received a second ASCT as salvage therapy at our center from March 1992 to December 2009. Eighty-one MM patients received a second ASCT for relapsed MM. The median time to relapse after first transplant was 39 months (9.83-100). All patients received reinduction therapy before the second ASCT. The high-dose regimen given before the second ASCT consisted of melphalan (MEL) alone in the majority. Complete response, very good partial response, and partial response were seen in 7.7%, 39.7%, and 50%, respectively, at day 100 post-ASCT; the median time to relapse after the second ASCT was 19 months. Early deaths occurred in 2.6%. Median progression-free survival (PFS) based on the time to myeloma relapse after first ASCT was 9.83 months (relapse ≤ 24 months) and 17.3 months (relapse ≥ 24 months) (P < .05). Median overall survival (OS) was 28.47 months (relapse ≤ 24 months) and 71.3 months (relapse >24 months) (P = .006). Second ASCT is a feasible and safe option for salvage therapy in MM. The best outcome was observed in patients whose time to progression was >24 months after first ASCT, as these patients had a subsequent PFS lasting over 1 year and an OS of almost 6 years.
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